Descriptions

Oxidative stress is the major driving force behind the aging process and many
age-related diseases. However, direct experimental evidence of whether antioxidants,
such as ascorbate (AA) and lipoic acid (LA) can slow the progression of aging process
and/or reduce risks of developing degenerative disease is largely absent. This suggests
a better understanding of the precise mechanism of how dietary micronutrient affect
parameters of involved in cellular redox balance and aging are warranted. In this
dissertation, young and old rats were used as our model to understand potential pro-oxidant
events that contribute to increases in oxidative stress in various tissues and
how antioxidants such as ascorbate and lipoic acid influence these events. Our major
findings are that the age-related impairment of mitochondria and increased deposition
of iron contribute significantly to heighten levels of oxidative stress, as evidenced by
the resultant increases in the rates of oxidant appearance and in the levels of oxidative
damage to DNA, lipids and proteins. We find that AA and LA strongly protected
against transition metal-ion dependent increases in oxidative stress. AA effectively
inhibited transition metal-mediated lipide peroxidation in human plasma. LA in its
reduced form effectively binds iron and copper in a redox inactive manner and
reversed chronically elevated levels of iron in the brain without removing enzyme
bound transition metal ions. LA also significantly attenuated the age-related increase
in oxidative stress associated with mitochondrial decay in the heart, as evidenced by
the improvements in AA levels and glutathione redox status. The declines in tissue
GSH levels in aged rats were strongly associated with the diminished γ-GCL activity
(in parallel with decreased expression of the catalytic and modulatory subunits), and
lowered Nrf2 expression and binding to ARE sequence in rat liver. Remarkably, all
these events were effectively reversed by the administration of LA, modulating the
parameters to return to the observed in young animals. The implications of this work
open new avenues not only for further understanding of the aging process but also for
possible strategies in its modulation by the micronutrients.